N-substituted urea inhibitors of farnesyl-protein transferase

Abstract

Novel halo-N-substituted urea compounds and pharmaceutical compositions are disclosed which are inhibitors of the enzyme, farnesyl protein transferase. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel halo-N-substituted urea compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammals such as a human.

What is claimed is:  
     
       1. A compound of the formula:                    
       or a pharmaceutically acceptable salt or solvate thereof, wherein: 
       A represents N or N-oxide;  
       X represents CH or C, such that when X is CH, there is a single bond to carbon atom 11 as represented by the solid line; or when X is C, there is a double bond to carbon atom 11, as represented by the solid and dotted lines;  
       X 1  and X 2  are independently selected from bromo or chloro, and X 3  and X 4  are independently selected from hydrogen, bromo or chloro provided that at least one of X 3  and X 4  is hydrogen;  
       Y 1  and Y 2  are independently selected from hydrogen or alkyl;  
       Z is ═O or ═S;  
       R 5 , R 6 , R 7  and R 8  each independently represents hydrogen, —CF 3 , alkyl or aryl, and further wherein R 5  may be combined with R 6  to represent ═O or ═S and/or R 7  may be combined with R 8  to represent ═O or ═S;  
       R 19  and R 20  are selected from: hydrogen, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, with the proviso that R 19  and R 20  are not both hydrogen;  
       v is zero, 1, 2 or 3; and  
       w is zero or 1.  
     
     
       2. The compound of  claim 1  wherein there is a single bond at carbon atom 11, X is CH, Z is ═O and R 5 , R 6 , R 7  and R 8  are hydrogen. 
     
     
       3. The compound of  claim 2  wherein X 1  is bromo, X 2  is chloro, X 3  is bromo and X 4  is hydrogen. 
     
     
       4. The compound of  claim 3  wherein Z is ═O; v is 1, w is 1, and Y 1  and Y 2  are hydrogen. 
     
     
       5. The compound of  claim 4  wherein R 19  a nd R 20  are independently selected from hydrogen, aryl and heterocycloalkyl wit h the proviso that R 19  and R 20  are not both hydrogen. 
     
     
       6. The compound of  claim 5  wherein; the aryl group is substituted with alkoxy; and the heterocycloalkyl group is substituted with —COOR 10  wherein R 10  is hydrogen or alkyl. 
     
     
       7. The compound of  claim 1  wherein there is a single bond at carbon atom 11, X is CH, Z is ═O, R 5 , R 6 , R 7  and R 8  are hydrogen, X 1  is bromo, X 2  is chloro, X 3  is bromo and X 4  is hydrogen, v is 1, w is 1, and Y 1  and Y 2  are hydrogen, R 19  and R 20  are independently selected from hydrogen, aryl and heterocycloalkyl; wherein the aryl group is substituted with alkoxy; and the heterocycloalkyl group is substituted with —COOR 10  wherein R 10  is hydrogen or alkyl, with the proviso that R 19  and R 20  are not both hydrogen. 
     
     
       8. A compound selected from the group consisting of:                  
                 
                   
     
     
       9. A compound selected from the group consisting of:                  
                   
     
     
       10. A pharmaceutical composition comprising an effective amount of compound of  claim 1  in combination with a pharmaceutically acceptable carrier. 
     
     
       11. A method of inhibiting farnesyl protien transferase in tumor cells expressing an activated ras oncogene comprising administering to a human in need thereof, a farnesyl protein transferase inhibiting amount of a compound of  claim 1 . 
     
     
       12. The method of  claim 11  wherein the tumor cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, prostate tumor cells, breast tumor cells or colon tumors cells. 
     
     
       13. A method of inhibiting farnesyl protein transferase comprising administering an effective amount of a compound of  claim 1  to a human in need thereof.